Ovarian cancer is the fifth most common cancer and the fourth leading cause of cancer death among women in the United States. Because of a lack of powerful screening and diagnostic tests, early detection has been difficult. Moreover, the molecular mechanisms important in ovarian cancer initiation, progression, and resistance to chemotherapeutic drugs remain largely unknown. We are using SAGE and other state-of-the-art molecular techniques to identify tumor markers and gain a greater understanding of the molecular pathways involved in ovarian tumorigenesis and cisplatin resistance. The analysis of gene expression in ovarian cancer suggests the involvement of many novel pathways in this disease. We are currently investigating the roles of different pathways using molecular and cellular approaches. Of particular interest is the involvement of claudin proteins and the role of tight junctions in ovarian cancer. Claudin proteins represent a large family of integral membrane proteins crucial for tight junction formation and function. Our SAGE data and follow-up experiments show that a few members of the claudin family are frequently elevated in all primary ovarian cancer subtypes and in many ovarian cancer cell lines but not in non-malignant ovarian cystadenomas. Although normally found at the membrane, these proteins are frequently mislocalized in cancer suggesting abnormal processing and a role in malignancy unrelated to known tight junction function. We are studying the role of these proteins by examining the effects of overexpression of wild type and mutant claudin proteins in ovarian cells. We are also examining the mechanisms of regulation of these proteins through phosphorylation. Our ultimate goal is the development of mechanism-based interventions for ovarian cancer patients. For example, we have recently found an important role for extracellular matrix (ECM) remodeling in the development of drug resistance in ovarian cancer. We have shown that tumor cells can remodel their microenvironment through production of collagen VI and that the presence of collagen VI increases resistance of ovarian cells to chemotherapeutic agents. Inhibition of ECM-cancer cell interactions may therefore provide novel therapeutic opportunities for the development of strategies to circumvent the problem of drug resistance in ovarian cancer. We are currently investigating the mechanisms of cell adhesion-mediated drug resistance (CAM-DR) in ovarian cancer. We are also studying the roles of the phosphatidylinositol 3 kinase/Akt pathway as well as the X-linked inhibitor of apoptosis (XIAP) pathway in ovarian cancer drug resistance using, among other approaches, siRNAs and somatic gene targeting strategies.